MGR ★ India, 20140522 07:45 Posting: # 12981 Views: 8,005 

Hi All, We are going for a 2stage approach for EMA using Potvin B method. Is this type of analysis can be done by WinNonlin 5.2 or 6.3? Moreover is there any articles/guidelines for the SAS code? Thanks in advance, — Regards, MGR 
d_labes ★★★ Berlin, Germany, 20140522 08:17 (edited by d_labes on 20140522 08:33) @ MGR Posting: # 12982 Views: 7,388 

Dear MGR, » We are going for a 2stage approach for EMA using Potvin B method. Welcome to the club . » Is this type of analysis can be done by WinNonlin 5.2 or 6.3? Do not have this software, but I think Helmut has posted here about this. You may find some material in his lectures also, some decided to the 2stage evaluation. » Moreover is there any articles/guidelines for the SAS code? AFAIK there is no decided article/guideline containing SAS code in this respect. But it should not that hard to code it: For stage 1 use the code for classical ABE for a 2x2 crossover, but instead of calculating 90% CIs derive the CIs to the confidence level (12*0.0294) = 94.12%. The power inspection step and the sample size estimation are a little bit hairy in SAS. Don't really know if Proc Power can be used for that. I suggest to use some tool external to SAS. You may guess what I recommend (if you ever have seen or heard about): Rpackage PowerTOST.For stage 2 evaluation (if a second stage becomes necessary) use a model with the effects:
Here my SAS code for that: Proc GLM data=yourdata; That is it. Not so difficult, isn't it? Hope this helps. BTW: There is a new revision of the EMA Q&A quite recently (09May2014) out there: EMA/618604/2008 Rev. 9 — Regards, Detlew 
Helmut ★★★ Vienna, Austria, 20140522 12:24 @ MGR Posting: # 12986 Views: 8,343 

Hi MGR, » Is this type of analysis can be done by WinNonlin 5.2 or 6.3? WinNonlin 5.2 is history (released in 2007, end of support of v5.2.1 was already in June 2011). In the following the procedure in Phoenix/WinNonlin’s 6.3 BE tool (EMA’s all fixed effects method and the additional term in the second stage according to the Q&Adocument Rev.7) and Example 2 from Potvin’s paper:
Intermediate power after stage 1 and sample size estimation for stage 2 in R with PowerTOST :
— Cheers, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
yjlee168 ★★ Kaohsiung, Taiwan, 20140523 21:17 (edited by yjlee168 on 20140524 08:35) @ Helmut Posting: # 13001 Views: 7,076 

Dear Detlew & Helmut, Sorry to cut in. Thank you both for the great summary of the twostage approach. It sounds like that it is possible to implement all these using R or into bear together with PowerTOST. » [...] » You should get: » CVintra: 0.1821 (=18.21%)OK, the example is from WLN. CV_{intra} = 18.21% (for C_{max}?) with 12 subjects. So it is not a HVD, is it? Does EMA or FDA accept the twostage BE if it is the case? » [...] » sampleN.TOST(alpha=0.0294, targetpower=0.80, theta0=0.95, CV=0.1821, design='2x2') Nice explanations and thank you both again. — All the best, Yungjin Lee bear v2.8.4: created by Hsinya Lee & Yungjin Lee Kaohsiung, Taiwan http://pkpd.kmu.edu.tw/bear Download link (updated) > here 
Helmut ★★★ Vienna, Austria, 20140523 22:39 @ yjlee168 Posting: # 13002 Views: 7,159 

Hi Yungjin, » […] It sounds like that it is possible to implement all these using R or into bear together with PowerTOST. Yes, why not? » OK, the example is from WLN. The example is from Potvin’s paper. » CV_{intra} = 18.21% (for C_{max}?) with 12 subjects. They didn’t state which PK metric the data covers. » So it is not a HVD, isn't it? The CV of the pooled data set (n=20) is 21.67%. So HVD is unlikely. » Does EMA or FDA accept the twostage BE if it is the case? Hopefully only in such cases (conventional unscaled ABE). I have heard that some people already — Cheers, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
MGR ★ India, 20140702 07:08 @ Helmut Posting: # 13199 Views: 6,746 

Hi Helmut, Here in our company WinNonlin 5.2.1 is installed, So i have to do analysis using the same version. Done the analysis, but the problem is that, 94.12% confidence interval values are coming same when subject(sequence) is treated as fixed effect and another with random effect. Could be please explain why this happened? I have attached the screen shot of the settings used. Thank you in advance. Edit: Subject line changed. [Helmut] — Regards, MGR 
Helmut ★★★ Vienna, Austria, 20140702 10:40 @ MGR Posting: # 13201 Views: 6,829 

Hi MGR, » Here in our company WinNonlin 5.2.1 is installed, So i have to do analysis using the same version. I don’t know how inspectors would judge the fact that your company is using an obsolete software (which is no more supported by Pharsight since 2011). The upgrade to Phoenix was free of charge for years. Talk to your management! » Done the analysis, but the problem is that, 94.12% confidence interval values are coming same when subject(sequence) is treated as fixed effect and another with random effect. As expected… » Could be please explain why this happened? The CI is calculated from the geometric mean ratio, the residual error, and the degrees of freedom (in a 2×2 crossover n–2, where n is the total number of subjects). These values are identical in both models.^{1} My results for the first stage of Potvin’s Example 2, Method B in Phoenix / WinNonlin 6.3 – agreeing with what the authors reported:
EMEA. The European Medicines Evaluation Agency. However, for the EMA you have to stick to the all fixed effects model with Subject(Sequence).^{2} My experiences from a last year’s MRP (mixed effects model, Method C passed BE in the first stage): Accepted by the RMS Germany; no comments from the CMS Austria, Denmark, Sweden, and The Netherlands. Nonetheless, Spain: “Statistical analysis should be GLM. Please justify.” Can you guess the outcome of the all fixed effects model presented in the response letter?
— Cheers, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
MGR ★ India, 20140703 06:32 @ Helmut Posting: # 13206 Views: 6,638 

Hi HS, Thank you very much for the explanation — Regards, MGR 